Garlic has been used in herbal medicine for thousands of years. Most studies on garlic during the past 15 years have been primarily in the field of cardiovascular. Cardiovascular studies have been mainly related to atherosclerosis, where effects of different garlic preparations garlic were examined on serum cholesterol, LDL, HDL, triglyceride, and oxidative stress. Agarwal, Med. Res. Rev. 16 (1): 111-124 (1996), Berthold and Sudhop, Curr. Opin. Lipido. 9 (6): 565-569 (1998); Ide and Lau, Phytomedicine 6 (2): 125-131 (1999). Although the studies were not consistent in relation to the dosage, standardization of garlic preparations, and period of treatment, most findings suggest but not strongly indicate that garlic decreases cholesterol and triglyceride levels in patients with increased levels of these lipids. Lowering of serum lipids by garlic ingestion may decrease the atherosclerosis process. The role of smooth muscle cell migration, proliferation in accelerated atherosclerosis and restenosis in ischemic heart disease patients was previously documented (J. American College Cardiology 15 (7): 1667-1687, 1990 and Human Pathology 18 (3): 240-247, 1987). Additionally, several studies showed antiplatelet effects for different garlic preparations and active ingredients, suggesting potential anti-thrombotic benefits (Apitz-Castro et. al., Thromb. Res. 75 (3): 243-249 (1994). The present investigation examined the possible role of garlic ingredients on smooth muscle cell migration toward plasma obtained from acute myocardial infarction I) patients during balloon angioplasty and stent coronary intervention & on the modulation of angiogenesis-mediated disorders.
Angiogenesis is the development of new blood vessels from preexisting blood vessels. Physiologically, angiogenesis ensures proper development of mature organisms, prepares the womb for egg implantation and plays a key role in wound healing. On the other hand, angiogenesis supports the pathological conditions associated with a number of disease states such as cancer, inflammation and ocular diseases (DR and AMD).
The development of vascular networks during embryogenesis or normal and pathological angiogenesis depends on growth factors and cellular interactions with the extracellular matrix (see Breier and Risau, Trends in Cell Biology, 6: 454-456(1996); Folkman, Nature Medicine 1:27-31(1995); Risau, Nature 386:671-674 (1997)). Blood vessels arise during embryogenesis by two processes: vasculogenesis and angiogenesis. Blood et al., Bioch. Biophys. Acta, 1032: 89-118 (1990). VEGF, bFGF, IL-8 and TNF-a are some of the growth factors that play a role in pathological angiogenesis associated with solid tumors, diabetic retinopathy, and rheumatoid arthritis. Folkman et al., Science, 235: 442-447 (1987). Angiogenesis is generally absent in adult or mature tissues, although it does occur in wound healing and in embryogenesis. Moses et al., Science, 248: 1408-1410 (1990).
Angiogenesis or “neovascularization” is a multi-step process controlled by the balance of pro- and anti-angiogenic factors. The latter stages of this process involve proliferation and the organization of endothelial cells (EC) into tube-like structures. Growth factors such as FGF2 and VEGF are thought to be key players in promoting EC growth and differentiation. The ECs is the pivotal component of the angiogenic process and responds to many cytokines through its cell surface receptors and intracellular signaling mechanisms. ECs in culture are capable of forming tube-like structures that possess lumens. Therefore, ECs are not only a prerequisite for neovascularization, but appear to be the basal structural requirement as well.
Angiogenesis-dependent diseases include the following: Inflammatory disorders such as immune and non-immune inflammation, rheumatoid arthritis, psoriasis; ocular disorders such as diabetic retinopathy, neovascular glaucoma, retinopathy of prematurity, age-related macular degeneration, corneal graft rejection; cancer associated disorders such as solid tumors, tumor metastases, and blood born tumors such as leukemia, angiofibroma, kaposi sarcoma, benign tumors, as well as other cancers, which require neovascularization to support tumor growth.
It has been proposed that inhibition of angiogenesis would be a useful therapy for restricting tumor growth. Inhibition of angiogenesis can be achieved by inhibiting endothelial cell response to angiogenic stimuli as suggested by Folkman et al., Cancer Biology, 3:89-96 (1992), where it was described examples of those endothelial cell response inhibitors such as angiostatic steroids, fungal derived products such fumagilin, platelet factor 4, thrombospondin, alpha-interferon, vitamin D analogs, and D-penicillamine. For additional proposed inhibitors of angiogenesis, see Blood et. al., Bioch. Biophys. Acta., 1032:89-118 (1990), Moses et al., Science, 248: 1408-1410 (1990), and U.S. Pat. Nos. 5,092,885, 5,112,946, 5,192,744, and 5,202,352. None of the inhibitors of angiogenesis described in the foregoing references target the use of garlic active ingredients in combination with antioxidants, and minerals for the inhibition of angiogenesis.
The inclusion of garlic in “nutraceutical” compositions has been previously proposed. For example, U.S. Pat. Nos. 5,883,086 (Craft) and 6,048,846 (Cochran) disclose compositions comprising the steroid hormone, dehydroepiandrosterone (DHEA), and optionally garlic. The '086 and '846 compositions are prescribed for the alleviation of an irregular heartbeat, the symptoms of stress and for lowering blood pressure in humans; and which modulate the physiological conditions within the body, respectively. U.S. Pat. No. 6,133,317 (Hart) discloses oxalic acid or oxalate compositions optionally further comprising garlic, for use in treating a myriad of ailments. U.S. Pat. No. 5,972,985 (Thomas et al.) discloses antioxidant compositions comprising a form of histidine and a group of antioxidant phytonutrients, e.g., garlic, for the treatment of a myriad of diseases. U.S. Pat. No. 5,332,579 discloses compositions comprising enzyme activating substances (i.e., magnesium), enzyme co-factors (i.e., B vitamins), an herbal antispasmodic substance (e.g., Valerian root), zinc and Vitamin C, for the treatment of alcoholic related disorders. The present invention compositions do not contain hormones, steroids, oxalic acid or oxalate, forms of histidine or antispasmodic substances.